3'-Azido-3'-deoxythymidine (AZT) is the only drug which is commercially available for the treatment of the acquired immune deficiency syndrome (AIDS) or symptomatic advanced AIDS-related complex (ARC). AZT inhibits the human immunodifficiency virus reverse transcriptase.
The main toxic affect of AZT in patients receiving the drug is severe anemia, often associated with a megaloblastic bone marrow (Yarchoan, et al., Lancet, 1986, 1:575).
AZT was found to consistently inhibit granulocyte macrophage colony forming cells and erythroid burst-forming cells in dose-dependent fashion in vitro (Sommadossi and Carlisle, Antimicrobial Agents Chemo., 1987, 31:453-454). The authors concluded that since prolonged AZT therapy will probably be required by an AIDS patient, such patients will be subject to increased myelosuppression.
In studies carried out in vitro to "rescue" human bone marrow progenitor (HBMP) cells using potential rescue agents, Sommadossi, et al., found that uridine and cytidine could reverse the toxic effect of AZT in HBMP cells. (Sommadossi, Carlisle, Schinazi, et al., Twenty-Seventh Intersci. Conf. Antimicrob. Agents Chemother. 1987; 27:163.)
While uridine is able to reverse the toxic effect of AZT on HBMP cells in vitro, unfortunately, uridine is deleterious to humans when given in vivo. When uridine is administered to a patient in an intermittant schedule, it is rapidly eliminated from the plasma. Continuous infusion of uridine is associated with rapid and potentially dangerous rises in body temperature. (See van Groeninger, et al., Cancer Treatment Rept., 70:745-750, 1986.)
The acyclouridine 5-benzylacylouridine (BAU) is an inhibitor of the enzyme uridine phosphorylase which is responsible for the cleavage of uridine to uracil. (Niedzwicki, et al., Biochem. Pharmacol., 1982 , 31:1857-1861.) BAU also inhibits the cleavage of the antineoplastic 5-fluoro-2'-deoxyuridine (Fd Urd) used in cancer chemotherapy because of its inhibition of the action of uridine phosphorylase (Chu, et al., Cancer Res., 1984, 44:1852-56.)
Dipyridamole (DPR) 2,6-(diethanol-amino)-4,8-dipyridino-pyridino-(5,4-d)pyrimidine is a platelet inhibitor which is used in prophylaxis of thromboembolism after cardiac valve replacement. (PDR.RTM., 42nd Ed., 1988, p.725.) There is also evidence which indicates that dipyridamole may inhibit the efflux of uridine from the cell. (Grem and Fisher, Cancer Res., 1986, 46:6191-6199; Grem and Fisher, Cancer Res., 1985, 45:2967-2972.)
It has been found that administration of a combination of BAU and dypyridamole to animals receiving AZT reduces the severity of AZT-induced anemia. Animals which were treated with AZT and with a combination of BAU and dipyridamole did not develop severe suppression of hemoglobin or hematocrit as did animals treated only with AZT. Administration of a combination of BAU/DPR is expected to produce a rise in the reticulocyte count, hemoglobin and hematocrit of patients which have previously been made anemic by administration of AZT.